Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a heterogeneous group of peripheral T-cell malignancies characterized by human T-cell leukemia virus type-1 infection, whose genetic profile has recently been fully investigated. However, it is still poorly understood how these alterations affect clinical features and prognosis. We investigated the effects of genetic alterations commonly found in ATL on disease phenotypes and clinical outcomes, based on genotyping data obtained from 414 and 463 ATL patients using targeted-capture sequencing and single nucleotide polymorphism array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequencies of and mutations, and many copy number alterations (CNAs), including amplifications and deletions, compared with indolent (chronic/smoldering) subtypes. By contrast, mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In a multivariate analysis incorporating both clinical factors and genetic alterations, the Japan Clinical Oncology Group prognostic index high-risk, older age, mutations, and amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, mutations, amplifications, and deletions were significantly associated with shorter survival, although the chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients.

Decreased RORC expression and downstream signaling in HTLV‐1‐associated adult T‐cell lymphoma/leukemia uncovers an antiproliferative IL17 link: A potential target for immunotherapy?

“…49 In ATL, PDL1 gene amplifications have been associated with worse prognosis, especially in aggressive subtypes. 50 For PDL1 transcript levels, we observed a trend for positive correlation to CD4+ cells (r = 0.66, p = 0.091) as well as proliferation (r = 0.66, p = 0.075) in our Brazilian ATL cohort (Subramanian et al unpublished), in agreement with a deleterious role for PD-L1. Again, combination immunotherapy by RORy agonists and PD-L1 blockade might be a more effective option in ATL, similar to the superior response rate to dual therapy with PD-1 and CTLA-4 blocking antibodies in advanced melanoma, as compared to monotherapy.…”

“…Conversely, inducing Th17 cell differentiation by RORy agonist LYC‐54143 simultaneously reduced PD‐1 + cell numbers and PD‐1 expression in vitro , and resulted in tumor growth inhibition in vivo in two murine models . In ATL, PDL1 gene amplifications have been associated with worse prognosis, especially in aggressive subtypes . For PDL1 transcript levels, we observed a trend for positive correlation to CD4+ cells ( r = 0.66, p = 0.091) as well as proliferation ( r = 0.66, p = 0.075) in our Brazilian ATL cohort (Subramanian et al .…”

Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T‐cell leukemia/lymphoma

“…The prognosis of each clinical subtype varies, and is estimated by clinical parameters of the ATLL prognostic index (ATL‐PI) or the indolent ATL‐PI (iATL‐PI) for the aggressive or indolent type, respectively . Kataoka et al recently reported that several genetic alterations, including IRF4 amplification, 9p24 ( PD‐L1 ) amplification, or 9p21 ( CDKN2A ) deletion, were significantly associated with poor prognosis in patients with the indolent type of ATLL. However, there is no fully established prognostic index that takes into account the molecular backgrounds of ATLL, and the molecular mechanisms responsible for such clinical diversity in ATLL are largely unknown.…”

Decreased RORC expression and downstream signaling in HTLV-1-associated Adult T-cell Lymphoma/Leukemia uncovers an antiproliferative IL17 link: a potential target for immunotherapy?

“…Also noteworthy is the induction of Th17 cell differentiation by RORy agonist LYC-54143, which simultaneously reduced PD-1 + cell numbers and PD-1 expression in vitro, resulting in tumor growth inhibition in two murine models 55 . PD-L1 amplifications have been associated with worse prognosis in ATL patients, especially in aggressive subtypes 56 .…”